The nuclear factor-κB (NF-κB) is a conditionally regulated transcription factor that plays a key role in the expression of a variety of genes involved in inflammation, cell survival, apoptosis, cell differentiation and cancer. It was first identified as a regulator of κ light chain expression in murine B-lymphocytes, but has now been shown to be expressed ubiquitously and to be a master regulator of several important processes. The NF-κB family consists of structurally related proteins of the Rel family, including p50, p52, p65/RelA, c-Rel and RelB (reviewed in Rothwarf and Karin, 1999). In unstimulated cells, NF-κB is bound to the inhibitor protein IκB, which masks the nuclear localisation signal of NF-κB and retains it in the cytoplasm. Activation of the cell with various stimuli initiates signalling pathways involving activation of a whole series of protein kinases. This results in phosphorylation of IκB, targeting the protein for degradation (Rothwarf and Karin, 1999). As a result, the. IκB/NF-κB complex dissociates, NF-κB translocates to the nucleus and binds to its cognate sites. Nuclear translocation of NF-κB is activated by various stimuli, including the inflammatory cytokines TNF-α and IL-1, UV-irradiation, mitogens, viruses, bacterias, double stranded DNA, ionizing radiation and hydrogen peroxide, in accordance with the important role played by NF-κB in various tissues (Rothwarf and Karin, 1999).
The functional importance of NF-κB in acute and chronic inflammation is based on its ability to regulate the promoters of a variety of genes. The products of such genes are e.g. cytokines, adhesion molecules and acute phase proteins, which are critical for inflammatory processes (Baeuerle et al., 1995, Shakov et al., 1990, Libermann et al., 1990). These findings are further underlined by the demonstration that mice containing targeted disruptions of the NF-κB subunits p50, RelB and c-Rel are compromised in various aspects of immune function and inflammatory processes (Sha et al., 1995; Weih et al., 1995, Köntgen et al.; 1995). Moreover, elevated levels of p65 have been observed in patients with rheumathoid arthritis and Inflammatory Bowel Disease (IBD). A role for NF-κB in inflammation was further established in a recent study, demonstrating that local administration of an antisense oligonucleotide targeted against the translational start site of NF-κB p65 abrogates established intestinal inflammation in mice (Neurath et al., 1996).
During the last years, it has become evident that redox regulation is an important mechanism that regulates conditional gene expression. Several transcription factors have been shown to be redox-regulated, including NF-κB. One common step in the activation mechanisms that lead to NF-κB translocation has been suggested to involve reactive oxygen species, based on the finding that NF-κB activation can be inhibited by a series of antioxidants (reviewed in Pitette et al., 1997). However, little is known about the pathways that activate and control NF-κB e.g. during oxidative stress.
Due to the involvement of the transcription factor NF-κB in inflammatory processes it could be possible to inhibit the expression of inflammatory cytokines and chemokines by affecting the function of the NF-κB in an animal or human.